Overexpression of HER2, a receptor tyrosine kinase (RTK) was found in approximately 30% of breast cancers and shown to correlate with the number of lymph node metastases and poor prognosis of the patients. HER2 overexpression leads to enhanced metastatic potential of breast cancer ceils, and poor clinical outcome of patients. Therefore, HER2 serves as an excellent target for the development of novel cancer therapies. Recently, CXCR4 was found to play a very important role in targeted metastasis of breast cancer. The malignant breast cancer cells are enriched for a chemokine receptor, CXCR4; and SDF-1 alpha, a natural ligand for CXCR4, is released in high amounts by certain organs, such as bone marrow, lung and liver. Our data show that HER2 can upregulate CXCR4 expression in breast cancer cells and the inhibition of CXCR4 function/or expression in HER2-overexpressing cancer cells suppresses HER2-induced malignancy. Therefore, our data provide a link between HER2 and CXCR4 in breast tumor progression and metastasis. Another important molecule COX2, a cyclooxygenase enzyme, is also involved in tumor invasion an( metastasis. Many RTKs have been found to locate in the nucleus, in spite of the fact that RTKs are traditionally known to be transmembrane cell surface proteins. Recently, using a cloning strategy for identification of targets for nuclear RTKs to understand their the biological significance and functions, we found that nuclear HER2 binds to a specific DNA element on the COX promoter and activates the promoter activity. The HER2-induced COX2 upregulation assembles the two important molecules involving in tumor progression. The long term goal of this proposal is to understand mechanisms for tumor progression and metastasis of breast cancer, specially, the roles of CXCR4 and COX2 in the HER2-mediated tumor progression and metastasis. In addition, we will investigate cellular mechanism of HER2 nuclear localization. Thus, three specific aims are proposed: Specific Aim 1: Tumor progression and metastasis of HER2-induced CXCR4 expression, Specific Aim 2: Tumor progression, metastasis and molecular mechanisms of HER2-induced COX2 expression, and Specific Aim 3: Cellular pathway for HER2 trafficking from cell surface membrane to nucleus and its effect on tumor progression and metastasis. Success of the proposal will further facilitate our better understanding in tumor progression and metastasis of breast cancer and may also provide a new avenue to comprehend functions and biological significances of nuclear RTKs, which have been overlooked in the past decades.